Inhibitie van histon-demethylases als een manier om de verminderde activiteit van DOT1L bij artrose te herstellen

Joint homeostasis is critically regulated by epigenetic mechanisms, particularly post-translational modifications of histones. Our team has identified that the enzyme DOT1L, through its methyltransferase activity on histone H3 at lysine 79 (H3K79me), plays a pivotal role in maintaining cartilage integrity and protecting against osteoarthritis (OA). While preserving or restoring H3K79me is essential for joint health, the regulatory mechanisms beyond DOT1L remain poorly understood. Although H3K79me is recognized for its role in transcriptional regulation, the specific histone demethylases responsible for modulating its levels have yet to be elucidated. This research aims to (1) identify the histone demethylases that regulate H3K79me in articular cartilage, (2) explore whether their pharmacological inhibition can mitigate H3K79me deficiency in OA, and (3) assess the therapeutic potential of this approach in countering disease progression. Additionally, we will review the current landscape of intra-articular drug therapies for OA, highlighting their translational relevance to epigenetic targets.